Peptic ulcers are one of the most prevalent diseases in industrialized nations. Control of gastric acid secretion is the main therapy for peptic ulcers. Acid secretion is in turn brought about by the interaction of three physiological stimulants, gastrin, acetylcholine and histamine with their respective parietal cell receptors. Prior to the discovery of histamine H.sub.2 -receptor antagonists such as cimetidine and ranitidine, peptic ulcer treatment consisted of antacid therapy and anticholinergic drugs (eg. dicyclomine HCl). However, with the advent of H.sub.2 -receptor antagonists, treatment with anticholinergic agents has been largely supplanted by histamine H.sub.2 -receptor antagonist therapy. The development of this class of therapeutic entities presents one of the most important advances in the field of medicinal chemistry.
Another major development in the treatment of peptic ulcers has been realized with the introduction of H.sup.+ /K.sup.+ -ATPase inhibitors e.g. omeprazole. The enzyme H.sup.+ /K.sup.+ -ATPase, which is also known as the proton pump, is located in the membrane of gastric parietal cells and is responsible for the transport of protons from blood to lumen, which in turn results in decreasing the pH of stomach contents which leads to aggravation of peptic ulcers.
Omeprazole itself is in fact a prodrug which under acidic conditions converts to the active drug, namely its corresponding sulfenamide. The mechanism of action of omeprazole is well-studied and is known to involve a nucleophilic attack of one (or two) thiol group(s) of the H.sup.+ /K.sup.+ -ATPase on the sulfur atom of the chemically active sulfenamide. The resulting chemical modification of the thiol group(s) of the enzyme (formation of a disulfide bond between the H.sup.+ /K.sup.+ -ATPase sulfur and the sulfur of the benzimidazole pyridinium salt) causes the observed inhibition of the proton pump. The complex cascade of molecular events that lead to the inhibition of the H.sup.+ /K.sup.+ -ATPase is shown in FIG. 1.
As shown in FIG. 1, the presence of acid is a prerequisite to the conversion of omeprazole to its chemically active sulfenamide. However, the resulting sulfenamide is a labile molecule which transforms further to a number of other compounds that are unreactive to nucleophilic attack by the H.sup.+ /K.sup.+ -ATPase thiol(s) and are therefore incapable of inhibiting the enzyme. These transformations are acid catalyzed. Accordingly, in a strict chemical sense, while acid is a prerequisite for the conversion of omeprazole to its active form, it also acts to its detriment. As a partial solution to this problem, omeprazole drug products are formulated to resist the acidic medium of the stomach by enteric coating. The coating is dissolved in the relatively neutral environment of the duodenum and omeprazole is absorbed into the blood stream which carries the prodrug to the proton pump. It should be emphasized however, that the conversion of the prodrug to the active enzyme inhibitor can only be achieved in acidic media which also results in substantial degradation of the active sulfenamide. In summary, the instability of omeprazole in acidic environments, which is a prerequisite to its activation into a proton pump inhibitor, is the major shortcoming of this drug.
Acid instability of omeprazole not only decreases the bioavailability of the drug, but also creates considerable difficulty in its formulation, adding to the cost of the final drug product.
These inherent problems are also observed in the large number of omeprazole analogues that have been synthesized to increase the acid stability of their corresponding sulfenamide. Two factors contribute to the instability of omeprazole in acidic media. First, as observed with other sulfoxides, omeprazole undergoes a characteristic acid catalyzed degradation known as the Pummerer rearrangement. Second, protonation of the trivalent nitrogen of sulfenamide followed by nucleophilic attack on the sulfur atom is another characteristic reaction of these compounds. Enzyme inhibition is observed only when the H.sup.+ /K.sup.+ -ATPase-S.sup.- acts as the nucleophile. On the other hand, sulfenamide degradation is caused when Cl.sup.- acts as the nucleophile. Accordingly, any slight gain in acid stability of the sulfenamide (or sulfoxide) that may be introduced by chemical modification (resistance to Cl.sup.- attack) is offset by a decrease in reactivity of the analogue to H.sup.+ /K.sup.+ -ATPase-S.sup.- attack. The net result is a less effective drug.
Another shortcoming of omeprazole is its variability of action in different patients. There is clinical evidence of a variable response to omeprazole as determined by inhibition of gastric acid release in peptic ulcer patients, attributable to a high first pass effect for the biotransformation of omeprazole, and the fact that the metabolism of omeprazole appears to be under polymorphic genetic control, resulting in variable amounts of drug reaching the systemic circulation following a given dose.